DX 9065A a novel, synthetic, selective and orally active inhibitor of factor Xa: in vitro and in vivo studies.

DX 9065A is the first member of a newly developed series of synthetic and selective inhibitors of factor Xa. DX 9065A inhibited in a dose-dependent manner human factor Xa with K iota value of 3.1 +/- 0.5 nM. Steady-state studies revealed that DX 9065A was a competitive inhibitor of factor Xa. DX 9065A inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway in vitro and in vivo. After i.v. injection to rabbits, DX 9065A displayed prolonged anti-factor Xa activity and inhibition of thrombin generation. Pretreatment of mice with DX 9065A dose-dependently improved the survival rate of mice injected with a lethal dose of tissue factor (ED50 = 1.1 +/- 0.2 mg/kg). After p.o. administration, DX 9065A caused a reduction in tissue factor-induced mortality of mice with ED50 value of 56 +/- 7 mg/kg. When given i.v. to rats, DX 9065A exhibited a dose-dependent antithrombotic effect against factor Xa + stasis-induced venous thrombosis (ED50 = 1.2 +/- 0.7 mg/kg i.v.), but also in an arteriovenous shunt thrombosis model (ED50 = 8.1 +/- 3.5 mg/kg i.v.) without affecting bleeding time significantly. Similar effects were obtained after s.c. or p.o. administration. In rabbits, after i.v., s.c. or p.o. administration, DX 9065A inhibited stasis-induced thrombosis after injection of tissue factor with ED50 values of 0.03 +/- 0.01, 0.3 +/- 0.07 and 50.5 +/- 19 mg/kg, respectively (n = 10). DX 9065A inhibited in a dose-dependent manner endotoxin-induced venous thrombosis in the rabbit (ED50 = 0.25 +/- 0.1 mg/kg i.v.) (n = 5) and reduced the decrease in platelet number and circulating fibrinogen levels in an experimental model of tissue factor-induced disseminated intravascular coagulation. Compared to standard heparin, DX 9065A exhibited a favorable antithrombotic/bleeding ratio, therefore showing that it might be considered as a promising compound in the treatment and prevention of various thrombotic diseases.